Balloon angioplasty, stents, and bypass surgery are commonly used to treat occlusive arterial disease, a leading worldwide cause of morbidity and mortality (de Vries et al., 2016). However, restenosis occurs in a significant number of the treated patients who develop intimal hyperplasia (Beamish et al., 2010; Dangas and Kuepper, 2002), in connection with which contractile smooth muscle cells (SMCs) decrease contractile protein expression and increase proliferation, migration, and extracellular matrix (ECM) production, which is characteristic of synthetic smooth muscle cells (contractile-to-synthetic phenotypic switching) (Beamish et al., 2010; Rensen et al., 2007). Small molecules that promote maintenance of the contractile phenotype or promote differentiation of contractile SMCs at the expense of synthetic SMCs (i.e., inhibit or reverse contractile-to-synthetic phenotypic switching) could minimize the development of intimal hyperplasia.
TGF-β1 and/or PDGF-BB are widely used to differentiate SMCs from human pluripotent stem cells (Bajpai et al., 2012; Cao et al., 2013; Cheung et al., 2012; Dash et al., 2015; Karamariti et al., 2013; Patsch et al., 2015; Wanjare et al., 2013; Yang et al., 2016; Zhang et al., 2011). However, up-regulation of PDGF-BB and TGF-β1 signaling promotes contractile-to-synthetic phenotypic SMC switching (Muto et al., 2007; Nabel et al., 1993; Newby and Zaltsman, 2000; Raines, 2004; Suwanabol et al., 2011; Wolf et al., 1994). As a result, if SMCs used in tissue engineered vascular constructs are generated from pluripotent stem cells using PDGF-BB and TGF-β1, the SMCs carry a risk of causing intimal hyperplasia.